Projektbeschreibung
Die Evolution antimikrobieller Resistenzen
Die Evolution von Eigenschaften in einer jeden Population hängt von drei Kräften ab: Geschichte, Zufall und Selektion. Bei antimikrobieller Resistenz in bakteriellen Krankheitserregern ist zwar der horizontale Gentransfer der wichtigste Verbreitungsweg, doch Belege aus Krankenhäusern auf der ganzen Welt deuten darauf hin, dass die Faktoren Geschichte und Zufall das Auftreten von Resistenzen in Grenzen halten. Im EU-finanzierten Projekt REPLAY soll nun an klinischen Stämmen des Bakteriums Klebsiella pneumoniae die Evolution von antimikrobieller Resistenz durch Plasmide erforscht werden. Das Forschungsteam wird mithilfe experimenteller Evolutionsanalysen und Gesamtgenomsequenzierung jeden evolutionären Faktor betrachten. Vor dem Hintergrund der medizinischen Herausforderungen, die antimikrobielle Resistenzen mit sich bringen, werden die Ergebnisse bessere Vorhersagen der Resistenzevolution sowie die Entwicklung neuer Interventionsstrategien ermöglichen.
Ziel
Antimicrobial resistance (AMR) in bacteria is one of the main challenges faced by modern medicine and understanding its evolution is urgently required. As any other evolved trait, three fundamental evolutionary forces guide the evolution of AMR: history, chance and selection. The specific role of each force determines whether, by what mechanism, and to what degree AMR evolves in a given population. Horizontal gene transfer is the main route for acquisition of AMR in bacterial pathogens and plasmids play a key role in the spread of resistant determinants. Of critical clinical importance is plasmid-mediated carbapenem-resistance in the Enterobacteriaceae family. The recurrent isolation of certain successful plasmid/bacterium associations in hospitals distributed worldwide is an example of how history and chance constrain the emergence of AMR. For example, pOXA-48 plasmid, encoding the OXA-48 carbapenemase, is frequently associated with the ST11 serotype of Klebsiella in hospitals around the world. Why is pOXA-48 restricted to a handful of clones if it can be mobilized to all K. pneumoniae serotypes? To answer this question, I am proposing a novel project that will analyze the impact of the three evolutionary forces in the evolution of plasmid-mediated AMR in clinical strains of K. pneumoniae. First, using experimental evolution and whole genome sequencing, I will quantitatively analyze the impact of each evolutionary force in AMR evolution. Also, I will study the adaptive mutational pathways leading to the compensation of plasmid-mediated costs. Then, I will use the novel high-throughput genetic screen CRISPRi, which allows silencing the expression of all chromosomal and plasmid genes one by one, to analyze the molecular basis determining the successful plasmid/bacterium associations. Altogether this cutting-edge proposal will greatly impact our ability to predict AMR evolution, paving the way for the development new intervention strategies to counteract AMR.
Wissenschaftliches Gebiet
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesmicrobiologybacteriology
- humanitieshistory and archaeologyhistory
- natural sciencesbiological sciencesevolutionary biology
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
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Aufforderung zur Vorschlagseinreichung
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
28034 Madrid
Spanien